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J. Biol. Chem., Vol. 282, Issue 2, 1384-1396, January 12, 2007

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Role for Neutral Sphingomyelinase-2 in Tumor Necrosis Factor -Stimulated Expression of Vascular Cell Adhesion Molecule-1 (VCAM) and Intercellular Adhesion Molecule-1 (ICAM) in Lung Epithelial Cells

p38 MAPK IS AN UPSTREAM REGULATOR OF nSMase2^*

From the Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425

Neutral sphingomyelinases (N-SMases) are major candidates for stress-induced ceramide production. However, there is little information on the physiological regulation and roles of the cloned N-SMase enzyme, nSMase2. In this study, nSMase2 was found to translocate acutely to the plasma membrane of A549 epithelial cells in response to tumor necrosis factor (TNF-) in a time- and dose-dependent manner. Additionally, TNF- increased N-SMase activity rapidly and transiently both endogenously and in cells overexpressing nSMase2. Furthermore, the translocation of nSMase2 was regulated by p38- MAPK, but not ERK or JNK, and the increase in endogenous N-SMase activity was abrogated by p38 MAPK inhibition. In addition, both p38- MAPK and nSMase2 were implicated in the TNF--stimulated up-regulation of the adhesion proteins vascular cell adhesion molecule-1 (VCAM) and intercellular adhesion molecule-1 (ICAM), but this was largely independent of NF-B activation. These data reveal p38 MAPK as an upstream regulator of nSMase2 and indicate a role for nSMase2 in pro-inflammatory responses induced by TNF- as a regulator of adhesion proteins.

Received for publication, September 28, 2006 , and in revised form, November 2, 2006.

^* This work was supported in part by National Institutes of Health Grant GM43825. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, 173 Ashley Ave., Charleston, SC 29425. Tel.: 843-792-4321; Fax: 843-792-4322; E-mail: hannun{at}musc.edu.

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